Megistus is an ancient, powerful alchemist, who had long dominated his fusion between science and magic when he saw first signs of the Final Crisis, as far as WWII. He, in response, started gathering transformative relics and artifacts related to alchemy, searching for a way to "protect" humanity. He decided that the cosmic cloud of red power that had created Red Kryptonite was a perfect means of doing this, and sent agents across time and space to retrieve the artifacts he needed to take the cloud to Earth. First, he sent Doctor Alchemy to retrieve the knowledge of the Library of Alexandria, which he had stolen in ancient times and sealed in a pocket dimension. Though Alchemy's plan to kill Superman was foiled, the wisdom and lore of the Library ended up within Alchemy's Philosopher's Stone, which ended in the hands of Megistus nonetheless, when Wonder Woman threw the stone into the sun-where Megistus had located his main base.

Megistus had, at one point, sent a powerful robotic agent to steal the H-Dial, the artifact capable of giving people superpowers; its guardian, Robby Reed, could hardly resist the machine's assault and ended up transforming back in New York, but before the Dial was lost to Megistus, he gave it to Tin of the Metal Men to wield against the monster. Tin, as Manbot the Mighty, was able to destroy the dragonic machine and save the Dial. Another of Megistus' efforts involved testing the power of the Orb of Ra during WWII, where his minions used it against the Blackhawks and a young team of the era, the Boy Commandos; while both teams escaped, Megistus managed to seize the Orb. A checkup the Doom Patrol had offered to run on the Flash's children was ruined when Megistus abducted Metamorpho, who was helping to stabilize the machinery. In Arthurian times, the Silent Knight teamed up with a timetravelling Superman to vanquish a dragon who held a powerful magical Eye Megistus sought. Some years before the main events, the Teen Titans suffered as an old foe of Aquaman fell under Megistus' control at Aquaman and Mera's wedding, and ultimately died in his quest for Atlantean magic. The Warlock of Ys was convinced to steal several ancient star charts; during the theft, he was sucked into a white star-Nth metal dimensional anomaly, and was sucked into another realm, from where he emerged by means of the pages of the Book of Destiny. Finally, the Challengers of the Unknown found in the book clues poining to Megistus involved in a final theft: Green Lantern's Power Battery.

Ultraman of Earth 3 was sent to New Earth to thwart Megistus' plans, but ended confronting Superman. However, bot resolved their differences and headed towards Sol to engage Megistus. In the journey there, however, Megistus turned the sun green with the Battery, depriving both Supermen of their powers. The Justice League and the Challengers of the Unknown reached the Sun with the Challengers' shuttle, and Green Lantern drained the green radiation with his ring, simultaneously charging it. Megistus defended his base with his transmutational and shapesifting powers, but while engaging the League the Challs freed Metamorpho and the also imprisoned Firestorm. June Masters of the Challengers also retrieved the Stone and Megistus' gloves; as Megistus continued to trade fisticuffs with the League, she threw herself out of an airlock and transmuted the cloud of cosmic radiation into harmless elements, apparently sacrificing herself in the process. In Earth, Megistus vanished, stating his role and damning the League for blocking his attempts to save humanity.

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